tra khoma

7/28/2019 Tra Khoma

1/7

Current Trachoma TreatmentMethodologiesFocus on Advancements in Drug Therapy

Loretta M. Chiu and Guy W. Amsden

Department of Adult and Pediatric Medicine, Clinical Pharmacology Research Center,Bassett Healthcare, Cooperstown, New York, USA

Abstract Currently, there are approximately 6 million people with irreversible blindnessas a result of chronic follicular conjunctivitis with subsequent corneal scarring

caused by Chlamydia trachomatis, also known as trachoma. On the basis of the

clinical studies evaluated, the most widely tested effective pharmacological treat-

ments for trachoma today are topical tetracycline 1% to be applied to both eyes

twice daily for 6 weeks or a single oral dose of azithromycin 20 mg/kg (up to 1g).

Although chemotherapy can generate prompt therapeutic response and surgery

can reverse the repercussions of these infections, these conditions will persist

through reinfections. Implementing proper personal hygiene and environmentalimprovement measures for the control of infection transmission will be essential

in reducing the potentially devastating results of trachoma infections.

CURRENT OPINION Drugs 2002; 62 (18): 2573-25790012-6667/02/0018-2573/$30.00/0 Adis International Limited. All rights reserved.

As one of the oldest infections known to man-

kind, trachoma was first documented in the phara-

onic era in Egypt.[1] Although understood to be a

chronic follicular conjunctivitis condition caused

by Chlamydia trachomatis that is susceptible to

several classes of antibacterials, it remains the

leading cause of preventable blindness world-wide.[2] Currently, there are approximately 6 mil-

lion people with irreversible blindness as a result

of trachoma; furthermore, an estimated 150 million

patients with active disease require treatment in

order to prevent this potential consequence.[1,3] It

is important to keep in mind that this apparently

ancient disease can have a considerable impact on

this generation because the majority of the infected

are paediatric patients. Since the ramification of

this condition bears such a significant yet prevent-able outcome, the World Health Organization

(WHO) has developed an alliance to spearhead the

elimination of trachoma globally by the year 2020

(GET 2020).[4-7] Other groups have joined in on

this mission to support the WHO alliance, such as

the International Trachoma Initiative (ITI) formed

by the Edna McConnell Clark Foundation and

Pfizer Inc., and to work with national programmes

in a small group of countries to expand trachomacontrol.

By adopting a comprehensive set of control

measures for trachoma in endemic areas, the fol-

lowing measures (identified by the acronym SAFE)

have been implemented: Surgery for trichiasis to

correct for the in-turned eyelashes; Antibiotics for

infectious trachoma; Face washing to reduce trans-

mission; and Environmental improvement through

advances in access to clean water and the control

of disease spreading flies.[8-10] A literature searchusing the terms trachoma, tetracycline, azithro-

mycin, erythromycin and doxycycline as well as a

7/28/2019 Tra Khoma

2/7

review of the Cochrane database and WHO web-

site lead to the review and selection of studies that

allowed the authors to summarise current treat-

ment methodologies and the science behind prov-

ing them when appropriate.

1. Trachoma Pathogenesisand Epidemiology

To understand the challenges that healthcare

providers need to overcome in the process of elim-

inating trachoma, it is important to first examinethe condition that is being dealt with. Trachoma

conjunctivitis is caused by C. trachomatis (sero-

types A, B, Ba or C) and is a chronic infection of

the eye.[11,12] The disease is marked by follicular

reaction in the superior tarsal conjunctiva that is

frequently associated with a concurrent papillary

response.[13] As the inflammatory response in the

follicles resolve, fine subconjunctival scars begin

to replace these structures. As the condition pro-

gresses, however, corneal involvement, includingthe development of a superior limbic pannus with

opacification of the corneal stroma and neo-

vascularisation, may occur. Often, the formation of

these scars contributes to the distortion of the tarsal

plate leading to in-turned eyelashes, also known as

trichiasis, which abrade the cornea. Such constant

irritation results in ulceration, scarring and, even-

tually, vision loss.[14] Currently, it is felt that the

amount of scarring is related to the intensity of the

follicular response as only repeated, severe disease

appears to predispose the patient to blindness.[6] It

is for this reason that appreciable scarring of the

conjunctivae and corneas do not appear until well

into the patients adult life despite many initial in-

fections that began in childhood.

Trachoma is identified commonly in large re-

gions of Africa, the Middle East, Southwest Asia,

the Indian subcontinent, the Aboriginal communi-

ties of Australia, and focal populations of Central

and South America. It is undoubtedly a disease of

poverty regardless of geographical region. Thispoint has been proven over time, as there has been

a strong historical connection between improve-

ment in socioeconomic factors and the disappear-

ance of endemic trachoma.[14]

The SAFE strategy addresses not only the short-

term treatment options but also the importance of

long-term prevention measures such as infection

control. Since the disease transmission in endemic

areas is through both direct and indirect hand-to-

eye contact, one can imagine that hygiene factors,

especially facial cleanliness and reduction of

household flies, are essential parameters in the

management of trachoma. Other common daily-

living events that predispose to infection trans-

mission include coughing and sneezing, and thesharing of bedding, handkerchiefs and towels.[15]

Although the WHO recommended treatments are

effective, measures to limit the rate of reinfection

remains a significant component that can limit the

success of the GET 2020 international alliance

efforts if not equally utilised.[4]

2. Treatment Strategies

2.1 SurgeryAlthough the recurrence of infection is not able

to be prevented by surgery, a large percentage of

trachomatous blindness could be prevented by the

pursuit of more timely trichiasis surgery.[16] The

lack of trained ophthalmologists is not such an ob-

stacle to a region as general practitioners or other

medical personnel can be trained to perform the

procedure appropriately.[17] The use of otherwise

helpful procedures, such as corneal transplanta-

tion, for advanced disease are often impossible,mainly because of the extent of eye involvement

from the infection, including entropion, keratinisa-

tion, and poor mucin and tear production.[6] For

these reasons, preventing future chlamydial infec-

tions along with trichiasis surgery, thus become the

most useful measures for eliminating the perma-

nent long-term repercussions of trachoma.

2.2 Medication

An evidenced based medicine approach reviewof the current treatment strategies for trachoma has

recently been published by the Cochrane Data-

2574 Chiu & Amsden

Adis International Limited. All rights reserved. Drugs 2002; 62 (18)

7/28/2019 Tra Khoma

3/7

base,[18] however, the following review provides

representative samples of recent trials to support

the use of the various trachoma treatment modali-

ties. Until recently, the mainstay approach to tra-

choma treatment has been the prolonged topical

application of tetracycline ointment or the use oforal erythromycin or doxycycline (see table I).[2]

However, because of the discomfort and blurred

vision that result from the topical treatments,[11]

along with the necessities of proper application

techniques and 6-week regimen durations, patient

compliance can often be less than optimal. Com-

pliance is often also complicated with the erythro-

mycin regimens because of the high incidence of

gastrointestinal adverse effects. Despite the activ-

ity of oral doxycycline against C. trachomatis, itssystemic administration has been associated with

permanent discolouration of the teeth during child-

hood development.[19] One of the advanced gener-

ation macrolides, azithromycin, has been demon-

strated to be an effective single-dose regimen as a

result of its prolonged half-life and has the poten-

tial to virtually eliminate the compliance issues

often associated with the topical ophthalmic re-

gimens. As it has a proven safety profile in the

paediatric population that is key to treating in theSAFE initiatives, and is far better tolerated than

oral erythromycin, this oral option as well as topi-

cal tetracycline have become WHO first-line treat-

ment options.

Although the effectiveness of both the oral and

topical treatment regimens is comparable, it has

been observed that lower recurrence rates may be

achieved with the administration of systemic anti-

bacterials.[11,20] This is because of the suspicion

that recurrence may be reflective of chlamydial in-

fection that is not limited to the eyes of children

with trachoma, but is also present in their naso-

pharynx and rectum.[11,21] For this reason, topical

antibacterial therapy may thus prove inadequate

because the remaining reservoirs of infection are

not eradicated and may indirectly promote reinfec-

tion of the disease.

As one of the first steps in assessing the utility

of azithromycin for trachoma, the ocular pharma-cokinetics of azithromycin were evaluated.

Karcioglu and colleagues characterised and com-

pared tear and serum concentrations of azithro-

mycin in 13 school-age children with active tra-

choma after a single 20 mg/kg dose of oral

azithromycin.[22] Peak tear and serum concentra-

tions of 1.53 and 0.153 mg/L, respectively, were

achieved within 12 hours of dose administration

and then subsequently declined gradually in both

sites over the course of the following 6 days. Atthe day 6 measurement, tear concentrations re-

mained detectable at a concentration of 0.21 mg/L,

Table I. Topical and oral treatment regimens for trachoma[13,14]

Route Medication Dosage

Topical Tetracycline 1% ointment Apply twice daily to both eyes for 6 weeks

Topical Tetracycline 1% ointment Apply daily to both eyes for 6 weeks

Topical Oxytetracycline/polymyxin Apply daily for 5 days every 4 weeks for 6 treatment cycles

Topical Oxytetracycline/polymyxin Apply twice daily for 8 weeks

Oral Azithromycin Single-dose 20mg/kg (up to 1g)

Oral Azithromycin One dose weekly for 3 weeks

Oral Azithromycin One dose every 4 weeks for 6 doses

Oral Azithromycin 10mg/kg daily for 3 doses

Oral Erythromycin Based on adult dose 250mg four times daily for 2 weeks, adjusted per kg

bodyweight for children with severe trachoma assigned to topical tetracycline arm

Oral Erythromycin 250mg four times daily or 500mg twice daily for 14 days for women of

childbearing age

Oral Doxycycline 100mg twice daily x 14 days avoid in children, pregnancy and breast feeding

Oral Amoxicillin 500mg three times daily x 14 days for women of childbearing age with

erythromycin intolerance

Treatment of Trachoma 2575


7/28/2019 Tra Khoma

4/7

which indicates that they exceeded the average

minimum inhibitory concentration (MIC) of 0.03

0.25 mg/L for C. trachomatis.[22] In a second study,

Tabbara et al. characterised the penetration of

azithromycin into tear fluid, aqueous humour and

conjunctival tissue specimens in 60 patients under-

going cataract surgery.[23] Patients received a sin-

gle 1g dose of oral azithromycin and had serum,

aqueous and tear specimens collected for up to 4

days after azithromycin administration, while con-

junctival tissue biopsy specimens continued to be

collected for up to 14 days. Resulting documented

concentration ranges were as follows: serum

0.0210.974 mg/L; tears 0.0822.892 mg/L; aque-

ous humour 0.010.07 mg/L; and conjunctival tis-

sue 0.732 g/g. The authors appropriately re-

ported that the detected concentrations in tears and

conjunctival tissue after 4 and 14 days, respec-

tively, exceeded the MIC90 (minimum concentra-

tion to inhibit growth of 90% of isolates) of C.

trachomatis following the single oral 1g dose of

azithromycin. However, since the study population

were undergoing cataract surgery rather than being

treated for an active ocular infection it is possible

the concentrations in the tissues/fluids of a patient

with trachoma may be even higher as a result of

the significant dependence on inflammation for

azithromycin delivery.[21,24]

In an interestingly designed, targeted treatment

study by Bowman et al., the efficacy of topical tet-

racycline (applied once by nurse in front of the

caregiver, then twice daily by the caregiver for 6

weeks) was compared to that of oral azithromycin20 mg/kg in an unsupervised environment in chil-

dren from 6 months to 10 years of age.[25] This

study design was an attempt to simulate practical

operational rather than ideal conditions and patient

outcomes were based solely on the incidence of

active trachoma. Among the 314 children who

were randomised between the two treatment arms,

those receiving azithromycin were significantly

more likely to achieve resolution of infection at

both 10 weeks (68 vs 51%, p = 0.007) and 6 months(88 vs 73%, p = 0.004). This was especially evident

in those with intense inflammation (p = 0.023). Al-

though the differences in efficacy at both follow-

up time points were significant in favour of

azithromycin, the investigators concluded that as a

result of the higher than expected resolution rates

associated with topical tetracycline in the absence

of supervision, the regular use of the more expen-

sive azithromycin was financially impractical in

the absence of medication donation program-

mes.[25] However, as stated before, this conclusion

would have been strengthened through the collec-

tion of recurrence rate data as the topical treatment

does not address other bodily reservoirs of the

pathogen.In a separate study by Dawson, et al., the effi-

cacy of topical oxytetracycline/polymyxin (once

daily for 5 days every 4 weeks for six treatment

cycles) was compared with several oral azithro-

mycin regimens (20 mg/kg given either once, once

weekly for 3 weeks, or once every 4 weeks for six

doses).[11] Although oral placebos were used for

the different azithromycin regimens, no placebo

was used for the topical treatment arm. The clinical

cure rates of the treatments were assessed at 2, 8and 12 months after the initiation of treatment.

Cures were defined primarily by the lack of active

trachoma but also secondarily by the presence or

absence of inclusion bodies on conjunctival smears.

The clinical cure rates were 35% at 2 months, 16%

at 8 months and 47% at 12 months. The pretreat-

ment chlamydial infection rate of 33% was de-

creased to 5% at 2 months and 9% at 12 months.

On the basis of the generated data, 16 doses of

azithromycin produced comparable results to 30

days of topical treatment. However, the authors

emphasised the significance of reinfection rates

observed at 1 year and the need to evaluate mass-

treatment protocols in order to control this endemic

disease.

3. Validation of MassTreatment Strategies

In the process of attempting to eliminate the dis-

ease, many studies have investigated recurrencerates in addition to the initial response rates to cur-

rent treatments.[2,11,12,26-28] The theory behind the

2576 Chiu & Amsden


7/28/2019 Tra Khoma

5/7

eradication of this infection from endemic areas is

based on the lower prevalence of the disease after

the administration of antibacterials; therefore, lo-

cal eradication of the disease can be achieved

through repeated, mass treatments.[6,7]

In a study by Laming et al., the impact of target

administration of single-dose (20 mg/kg) oral

azithromycin to Aboriginal children and their co-

resident sibling contacts (ages 6 months to 15

years) was characterised and the results were

placed in the context of whole-community treat-

ment strategy (i.e., SAFE) as recommended by the

WHO.[27] Acute trachoma prevalence dropped

from a baseline of 42% to 22% at 6 months and to

31% at 12 months. Further treatment was given to

those who still had trachoma at 12 months, which

resulted in a point-prevalence at 24 months of

34%. Prevalence in pre-schoolchildren who were

sibling contacts to the infected schoolchildren

dropped from a baseline of 55% to 25% at 6

months. The authors concluded from their research

that rather than proceeding with mass-treatment

strategies, appropriate screening followed by treat-ment of identified patients leads to a significant

decrease in trachoma prevalence in a community.

They also recommended that these treatment strat-

egies be combined with appropriate health promo-

tion and attempts to improve living conditions to

try to minimise ongoing prevalence not eradicated

by treatment.[27]

Because of the substantial rate of reinfection

concluded from published trials that evaluated

azithromycin,[2,11,29] Fraser-Hurt et al. comparedthe 2, 6 and 12 month prevalence rates of active

trachoma when villagers from eight Gambian vil-

lages were mass-treated with either oral azithro-

mycin (weekly for three doses) versus topical tet-

racycline (daily for 6 weeks).[12] All villagers who

were present for the pre-treatment survey were el-

igible to participate. The villages were matched in

pairs of similar size and treatment regimen was

allocated randomly within these pairs. At baseline,

16% of the studied villagers were trachoma-positive,defined as the presence of either follicular disease

or intense disease as judged by experienced tropi-

cal ophthalmologists. Two months after treatment,

the prevalence in both groups was approximately

5%. At the 12-month evaluation it was noted that

those who had received tetracycline had a preva-

lence of 16% compared with only 7.7% for those

treated with azithromycin. In addition, there were

fewer new prevalent cases in the azithromycin

group at 12 months and a significantly better rate

of trachoma resolution. On the basis of their data,

these authors concluded that the convenience of

azithromycin may allow for higher coverage than

has been previously achieved with standard treat-

ments.

In a study by Schachter et al., pairs of villages

in trachoma endemic areas of Egypt, Gambia and

Tanzania were matched on trachoma rates in chil-

dren aged 110 years.[28] The matching villages in

each area were randomised to receive either 6

weeks of daily topical tetracycline ointment or

three weekly doses of azithromycin. Thereafter,

the villagers had clinical examinations at approxi-

mately 3 and 12 months after their baseline exam-

ination and start of treatment. C. trachomatis wasidentified by ligase chain reaction (LCR). Of the

study participants who were initially LCR posi-

tive, 95% of those who had taken at least one dose

of azithromycin were negative at the 3-month fol-

low-up exam compared with 82% of those who

received at least 28 days of topical tetracycline. At

the 1-year follow-up point, village-wide positivity

rates had decreased more substantially in all three

geographic areas when the participants received

azithromycin compared with tetracycline. Clinicalactivity was also reduced substantially in those vil-

lages that received azithromycin. The authors con-

cluded that the community-wide use of azithro-

mycin markedly reduces infection rates and

clinical trachoma in endemic areas, and that it may

be an important approach to trachoma control.

Keeping in mind that trachoma is initiated

through an infectious process, the use of antibac-

terials becomes a logical therapeutic step that can

also serve to limit the spread of this condition. Cur-rently, the WHO recommends that all children in

communities with more than 20% of children pre-



7/28/2019 Tra Khoma

6/7

senting with signs and symptoms of active tra-

choma require antibacterial therapy as part of a

mass treatment strategy.[11,12] However, there has

been a lot of debate surrounding this issue. On one

hand, antibacterials can certainly reduce the num-

ber and the overall reservoir pool of ocular

chlamydial infections within a community and

thus contribute to the decline in transmission rates.

However, the persistence of the diseases preva-

lence as a result of reinfection warrants concern for

the eventual development ofC. trachomatis strains

that may carry antibacterial resistant character-

istics. Recent data presented by Lietman et al. in1998 predicts that in regions where trachoma prev-

alence in children is below 35%, annual or biennial

mass treatment would be adequate in eliminating

trachoma.[30] However, for areas with prevalence

above 35%, biannual mass treatment may be indi-

cated. It is important to note that these estimations

assume the universal availability of medication

treatments along with no immigration of infected

individuals to these villages that have undergone

universal treatment.

4. Expert Opinion

On the basis of the clinical studies evaluated,

the most widely tested effective treatment strate-

gies for ocular trachoma at this time include topical

tetracycline 1% to be applied to both eyes twice

daily for 6 weeks or a single oral dose of azithr-

omycin 20mg/kg (up to 1g). Although chemother-

apy can generate prompt therapeutic response andsurgery can reverse the repercussions of these in-

fections; these conditions will persist through rein-

fections. Implementing proper personal hygiene

and environmental improvement measures for the

control of infection transmission will be essential

in order to meet the goals of GET2020.[31]

Acknowledgements

No funding source was available for the production of

this manuscript. Dr Chiu has no conflicts of interest concern-

ing this topic. Dr Amsden is a consultant and researcher for

Pfizer, Inc. on azithromycin but not for trachoma indications.

References1. Available from URL: http://www.who.int/pbd/trachoma/in-

trod.htm [Accessed 2001 Dec]2. Bailey RL, Arullendran P, Whittle HC, et al. Randomised con-

trolled trial of single-dose azithromycin in treatment of tra-

choma. Lancet 1993; 342: 453-6

3. Thylefors B, Negrel AD, Pararajasegaram R, et al. Global dataon blindness. Bull World Health Organ 1995; 73: 115-21

4. Bailey RL, Lietman T. The SAFE strategy for the eliminationof trachoma by 2020: will it work? Bull World Health Organ2001; 79: 233-6

5. Negrel AD, Mariotti SP. WHO alliance for the global elimina-tion of blinding trachoma and the potential use of azithro-mycin. Int J Antimicrob Agents 1998; 10: 259-62

6. Lietman T,Fry A. Can we eliminate trachoma? BrJ Ophthalmol2001; 85: 385-7

7. Lietman TM. Trachoma control: the end of the beginning? Oph-

thalmology 2001; 108: 2163-48. Mabey D, Fraser-Hurt N. Trachoma. BMJ 2001; 323: 218-21

9. West S, Munoz B, Lynch M, et al. Impact of face-washing on

trachoma in Kongwa, Tanzania. Lancet 1995; 345: 155-8

10. Taylor HR. A trachoma perspective. Ophthalmic Epidemiol2001; 8: 69-72

11. Dawson CR, Schachter J, Sallam S, et al. A comparison of oralazithromycin with topical oxytetracycline/polymyxin for thetreatment of trachoma in children. Clin Infect Dis 1997; 24:

363-8

12. Fraser-Hurt N, Bailey RL, Cousens S, et al. Efficacy of oralazithromycin versus topical tetracycline in mass treatment of

endemic trachoma. Bull World Health Organ 2001; 79: 632-40

13. OBrien TP. Conjunctivitis. In: Mandell GL, Bennett JE, Dolin

R, editors. Mandell, Douglas and Bennetts principles andpractice of infectious disease. Philadelphia (PA): ChurchillLivingstone, 2000: 1253-6

14. Jones RB, Batteiger BE. Chlamydia trachomatis. In: MandellGL, Bennett JE, Dolin R, editors. Mandell, Douglas and Ben-

netts principles and practice of infectious disease. Philadel-phia (PA): Churchill Livingstone, 2000: 1989-2004

15. Emerson PM, Cairncross S, Bailey RL, et al. Review of theevidence base for the F and E components of the SAFEstrategy for trachoma control. Trop Med Int Health 2000; 5:515-27

16. Taylor HR. Trachoma. Int Ophthalmol 1990; 14: 201-4

17. Taylor HR. Development of immunity to ocular chlamydial in-fection. Am J Trop Med Hyg 1990; 42: 358-64

18. Mabey D, Fraser-Hurt N. Antibiotics for trachoma. CochraneDatabase of Systematic Reviews. Available in The CochraneLibrary [database on disk and CD ROM]. Updated quarterly.

The Cochrane Collaboration; issue 2. Oxford Update Soft-ware, 2002

19. Tabbara KF. Blinding trachoma: the forgotten problem. Br JOphthalmol 2001; 85: 1397-9

20. Dawson CR, Schachter J. Strategies for treatment and controlof blinding trachoma: cost-effectiveness of topical or sys-temic antibiotics. Rev Infect Dis 1985; 7: 768-73

21. Duran JM, Amsden GW. Azithromycin: indications for the fu-ture? Exp Opin Pharmacother 2000; 1: 489-505

22. Karcioglu ZA, El-Yazigi A, Jabak MH, et al. Pharmacokineticsof azithromycin in trachoma patients. Ophthalmology 1998;105: 658-61

23. Tabbara KF, Al-Kharashi SA, Al-Mansouri SM, et al. Ocularlevels of azithromycin. Arch Ophthalmol 1998; 116: 1625-8

24. Amsden GW, Nafziger AN, Foulds G. Pharmacokinetics in se-rum and leukocyte exposures of oral azithromycin, 1500 mil-

2578 Chiu & Amsden


7/28/2019 Tra Khoma

7/7

ligrams, given over a 3 or 5 day period in healthy subjects.Antimicrob Agents Chemother 1999; 43: 163-5

25. Bowman RJ, Sillah A, Van Dehn C, et al. Operational compar-ison of single-dose azithromycin and topical tetracycline fortrachoma. Invest Ophthalmol Vis Sci 2000; 41: 4074-9

26. Guzey M, Aslan G, Ozardali I, et al. Three-day course of oralazithromycin vs topical oxytetracycline/polymyxin in treat-ment of active endemic trachoma. Jpn J Ophthalmol 2000;44: 387-91

27. Laming AC, Currie BJ, DiFrancesco M, et al. A targeted, sin-gle-dose azithromycin strategy for trachoma. Med J Aust2000; 172: 163-6

28. Schachter J, West, SK, Mabey D, et al. Azithromycin in controlof trachoma. Lancet 1999; 354: 630-5

29. Tabbara KF, El-Asrar AMA, Al-Omar O, et al. Single-doseazithromycin in the treatment of trachoma. Ophthalmology1996; 103: 842-6

30. Lietman TM. Mass antibiotics in trachoma control: whom shall

we treat how often? In: Stephens RS, editor. Chlamydial in-

fections. Proceedings of the ninth international symposiumon human chlamydial infection. San Francisco (CA): Interna-

tional Chlamydia Symposium, 1998 : 359-62

31. Frick KD, West SK. The SAFE strategy for trachoma control:

planning a cost-effectiveness analysis of the antibiotic com-

ponent and beyond. Ophthalmic Epidemiol 2001; 8: 205-14

Correspondence and offprints: Dr Guy W. Amsden, Clinical

Pharmacology Research Center, Bassett Healthcare, One

Atwell Road, Cooperstown, New York 13326, USA.E-mail: [email protected]



tra khoma

Documents